CN114349684A - Synthetic method of benzo [ c, d ] indole imine derivative - Google Patents
Synthetic method of benzo [ c, d ] indole imine derivative Download PDFInfo
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- CN114349684A CN114349684A CN202210060255.1A CN202210060255A CN114349684A CN 114349684 A CN114349684 A CN 114349684A CN 202210060255 A CN202210060255 A CN 202210060255A CN 114349684 A CN114349684 A CN 114349684A
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- benzo
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- derivative
- derivatives
- indoleimine
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- 125000005605 benzo group Chemical group 0.000 title claims abstract description 40
- -1 indole imine Chemical class 0.000 title claims description 21
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims description 9
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims description 9
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims description 9
- 238000010189 synthetic method Methods 0.000 title claims 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 239000002904 solvent Substances 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000003054 catalyst Substances 0.000 claims abstract description 18
- 239000000654 additive Substances 0.000 claims abstract description 13
- 150000002527 isonitriles Chemical class 0.000 claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 8
- MLAXVEHWMLUSFO-UHFFFAOYSA-N indol-2-imine Chemical class C1=CC=CC2=NC(=N)C=C21 MLAXVEHWMLUSFO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 230000000996 additive effect Effects 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- 238000001308 synthesis method Methods 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Chemical group 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 229910002666 PdCl2 Inorganic materials 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims 1
- 239000012299 nitrogen atmosphere Substances 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 230000002526 effect on cardiovascular system Effects 0.000 abstract description 3
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 208000026106 cerebrovascular disease Diseases 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 238000012216 screening Methods 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 229910052723 transition metal Inorganic materials 0.000 abstract description 2
- 150000003624 transition metals Chemical class 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- HYNQXOLPKHMRGL-UHFFFAOYSA-N 8-iodonaphthalen-1-amine Chemical class C1=CC(I)=C2C(N)=CC=CC2=C1 HYNQXOLPKHMRGL-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 5
- FAGLEPBREOXSAC-UHFFFAOYSA-N tert-butyl isocyanide Chemical compound CC(C)(C)[N+]#[C-] FAGLEPBREOXSAC-UHFFFAOYSA-N 0.000 description 4
- 101150003085 Pdcl gene Proteins 0.000 description 3
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- FKFCNFNWFJYIJU-UHFFFAOYSA-N 8-bromonaphthalen-1-amine Chemical class C1=CC(Br)=C2C(N)=CC=CC2=C1 FKFCNFNWFJYIJU-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 101150050192 PIGM gene Proteins 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- WQFPYEBGLBCQOY-UHFFFAOYSA-N 1-isocyano-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C([N+]#[C-])C=C1 WQFPYEBGLBCQOY-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- DGWFDTKFTGTOAF-UHFFFAOYSA-N P.Cl.Cl.Cl Chemical compound P.Cl.Cl.Cl DGWFDTKFTGTOAF-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- XYZMOVWWVXBHDP-UHFFFAOYSA-N cyclohexyl isocyanide Chemical compound [C-]#[N+]C1CCCCC1 XYZMOVWWVXBHDP-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- BWHXBNDMKJOQIE-UHFFFAOYSA-N indole-2-thione Chemical class C1=CC=CC2=NC(=S)C=C21 BWHXBNDMKJOQIE-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- BRMYZIKAHFEUFJ-UHFFFAOYSA-L mercury diacetate Chemical compound CC(=O)O[Hg]OC(C)=O BRMYZIKAHFEUFJ-UHFFFAOYSA-L 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004983 proton decoupled 13C NMR spectroscopy Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Indole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种多取代苯并[c,d]吲哚亚胺衍生物的合成方法，首先将8‑卤‑1‑萘胺类化合物、异腈类衍生物、催化剂和添加剂置于反应容器中，再在反应容器中加入溶剂至8‑卤‑1‑萘胺类化合物完全溶解，然后在氮气氛围中加热进行反应，反应结束后经过后处理得到所述的多取代苯并[c,d]吲哚亚胺衍生物。本发明采用“一锅一步法”合成多取代苯并[c,d]吲哚亚胺衍生物，使用高效的过渡金属作为催化剂，反应条件简单，操作方便，底物普适性广泛，反应原料简单易得，生产成本低廉，不仅适用于实验室小规模制备，还适用于工业化大规模生产。该反应有利于多取代苯并[c,d]吲哚亚胺衍生物化合物库的建立，为抗肿瘤，抗菌和治疗心脑血管疾病等活性筛选提供了很简便的方法。The invention discloses a method for synthesizing multi-substituted benzo[c,d]indoleimine derivatives. First, 8-halogen-1-naphthylamine compounds, isonitrile derivatives, catalysts and additives are reacted In the container, then in the reaction vessel, add solvent until the 8-halogen-1-naphthylamine compound is completely dissolved, then heat in a nitrogen atmosphere to react, and after the reaction finishes, the described polysubstituted benzo[c, d] Indoleimine derivatives. The invention adopts "one-pot one-step method" to synthesize multi-substituted benzo[c,d]indoleimine derivatives, uses efficient transition metal as catalyst, has simple reaction conditions, convenient operation, wide substrate universality, and reaction raw materials. It is simple and easy to obtain, and has low production cost, and is not only suitable for small-scale laboratory preparation, but also suitable for industrial large-scale production. This reaction is beneficial to the establishment of the compound library of polysubstituted benzo[c,d]indoleimine derivatives, and provides a simple method for the screening of antitumor, antibacterial and cardiovascular and cerebrovascular diseases.
Description
技术领域technical field
本发明属于有机合成领域，尤其涉及一种苯并[c,d]吲哚亚胺衍生物的合成方法。The invention belongs to the field of organic synthesis, in particular to a method for synthesizing a benzo[c,d]indoleimine derivative.
背景技术Background technique
苯并[c,d]吲哚类化合物是一类重要的杂环化合物，该类化合物由于具有很好的生物活性和光学性能被广泛的应用于生物医药(J.Med.Chem.1991,34,1925；Bioorg.Med.Chem.2012,20,789；J.Med.Chem.1992,35,663.)、荧光染料(Org.Lett.2015,17,278.)、有机配体(Tetrahedron 1996,52,7277.)和材料(Dyes Pigm.2016,129,163；Dyes Pigm.2017,141,457.)等方向。苯并[c,d]吲哚亚胺衍生物是一类特殊的苯并[c,d]吲哚类化合物，对抑制肿瘤细胞增殖具有良好的活性和选择性(中国发明专利,101602707,16Dec 2009.)，而且还被用作心脑血管药物(Eur.Pat.Appl.,446603,18Sep 1991)。Benzo[c,d]indole compounds are an important class of heterocyclic compounds, which are widely used in biomedicine due to their good biological activity and optical properties (J.Med.Chem.1991,34 , 1925; Bioorg.Med.Chem.2012,20,789; J.Med.Chem.1992,35,663.), fluorescent dyes (Org.Lett.2015,17,278.), organic ligands (Tetrahedron 1996,52,7277.) and materials (Dyes Pigm. 2016, 129, 163; Dyes Pigm. 2017, 141, 457.) and other directions. Benzo[c,d]indoleimine derivatives are a special class of benzo[c,d]indole compounds with good activity and selectivity for inhibiting tumor cell proliferation (Chinese Invention Patent, 101602707, 16Dec 2009.), but also used as a cardiovascular and cerebrovascular drug (Eur.Pat.Appl., 446603, 18Sep 1991).
构建苯并[c,d]吲哚亚胺衍生物的方法主要有两种：一种是以苯并[c,d]吲哚-2-酮为原料，首先对氮原子进行基团修饰，然后和五硫化二磷反应生成苯并[c,d]吲哚-2-硫酮衍生物，最后在氧化汞或醋酸汞的催化下与伯胺类化合物反应生成苯并[c,d]吲哚亚胺衍生物。该反应步骤多，使用剧毒性催化剂，具有一定危害性。另一种方法也是以苯并[c,d]吲哚-2-酮为原料，以三氯氧膦为脱水剂，首先和伯胺类化合物进行脱水缩合反应形成亚胺，最后对氮原子进行基团修饰得到多取代苯并[c,d]吲哚亚胺衍生物。通过上述两种方法，我们得知苯并[c,d]吲哚-2-酮的固有结构不容易进行修饰，导致目前报道的苯并[c,d]吲哚亚胺衍生物数量较少。因此，该项发明旨在发明一种简单的方法使用高效金属作为催化剂制备一类新型苯并[c,d]吲哚亚胺衍生物。There are two main methods for the construction of benzo[c,d]indolimine derivatives: one is to use benzo[c,d]indol-2-one as raw material, and firstly, group modification is performed on the nitrogen atom. Then it reacts with phosphorus pentasulfide to generate benzo[c,d]indole-2-thione derivatives, and finally reacts with primary amines under the catalysis of mercury oxide or mercuric acetate to generate benzo[c,d]indoleimine derivative. This reaction has many steps and uses a highly toxic catalyst, which is harmful to a certain extent. Another method also uses benzo[c,d]indol-2-one as raw material and phosphine trichloride as dehydrating agent. First, it is dehydrated and condensed with primary amine compounds to form imines, and finally nitrogen atoms are dehydrated. Group modification to obtain polysubstituted benzo[c,d]indoleimine derivatives. Through the above two methods, we know that the inherent structure of benzo[c,d]indol-2-one is not easy to be modified, resulting in a small number of reported benzo[c,d]indolimine derivatives. . Therefore, this invention aims to invent a simple method to prepare a new class of benzo[c,d]indoleimine derivatives using efficient metals as catalysts.
发明内容SUMMARY OF THE INVENTION
本发明的目的是针对现有技术的不足，提供了一种苯并[c,d]吲哚亚胺衍生物的合成方法。The object of the present invention is to provide a method for synthesizing benzo[c,d]indoleimine derivatives in view of the deficiencies of the prior art.
本发明的目的是通过以下技术方案来实现的：一种苯并[c,d]吲哚亚胺衍生物的合成方法，包括以下步骤：在催化剂和添加剂的作用下，8-卤-1-萘胺类化合物和异腈类衍生物在溶剂中氮气氛围一定温度下发生反应，反应结束后经过后处理得到所述的苯并[c,d]吲哚亚胺衍生物；The object of the present invention is achieved through the following technical solutions: a method for synthesizing benzo[c, d] indoleimine derivatives, comprising the following steps: under the action of catalysts and additives, 8-halogen-1- The naphthylamine compound and the isonitrile derivative react under a certain temperature in a nitrogen atmosphere in a solvent, and after the reaction is completed, the benzo[c,d]indoleimine derivative is obtained by post-processing;
所述的8-卤-1-萘胺类化合物的结构如式(I)所示：The structure of the 8-halo-1-naphthylamine compound is shown in formula (I):
所述的异腈类衍生物的结构如式(II)所示：The structure of the isonitrile derivatives is shown in formula (II):
R4-NC (II)R 4 -NC (II)
所述的苯并[c,d]吲哚亚胺衍生物的结构如式(III)所示：The structure of the benzo[c,d]indoleimine derivative is shown in formula (III):
式(I)～(III)中，R1选自H、芳基、烷基、磺酸基或酰基；In formulas (I) to (III), R 1 is selected from H, aryl, alkyl, sulfonic acid or acyl;
R2选自H、烷基、酰基、硝基或氨基；R 2 is selected from H, alkyl, acyl, nitro or amino;
R3选自H、烷基、酰基、硝基或氨基；或者R2、R3和与其相连的萘环上的碳共同形成五元环或六元环；R 3 is selected from H, alkyl, acyl, nitro or amino; or R 2 , R 3 and the carbon on the naphthalene ring connected to it together form a five-membered ring or a six-membered ring;
R4选自烷基、苯基或萘基；R 4 is selected from alkyl, phenyl or naphthyl;
X选自卤素原子；X is selected from halogen atoms;
其中，苯基上的取代基选自C1～C4烷基、C1～C4烷氧基、硝基或卤素。Wherein, the substituent on the phenyl group is selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro or halogen.
作为优选，R1选自H、苯基、甲基、乙基、正丁基、苯磺酰基、萘磺酰基、噻吩磺酰基或苯甲酰基；Preferably, R 1 is selected from H, phenyl, methyl, ethyl, n-butyl, benzenesulfonyl, naphthalenesulfonyl, thiophenesulfonyl or benzoyl;
R2选自H、硝基或氨基；R 2 is selected from H, nitro or amino;
R3选自H、硝基或氨基；或者R2、R3都为亚甲基，并且这两个亚甲基以化学键相连；或者R2、R3都为甲酰基，并且这两个甲酰基都和氮以化学键相连形成己内二酰胺；R 3 is selected from H, nitro or amino; or both R 2 and R 3 are methylene groups, and the two methylene groups are connected by a chemical bond; or both R 2 and R 3 are formyl groups, and the two methyl groups are Acyl groups are linked to nitrogen to form caprolactam;
R4选自叔丁基、环己基、正丁基、苯基、萘基、对甲苯基、对硝基苯基、对氯苯基、对氟苯基、3,4-二氯苯基、对甲氧苯基或邻氯苯基；R 4 is selected from tert-butyl, cyclohexyl, n-butyl, phenyl, naphthyl, p-tolyl, p-nitrophenyl, p-chlorophenyl, p-fluorophenyl, 3,4-dichlorophenyl, p-methoxyphenyl or o-chlorophenyl;
X选自碘、溴。X is selected from iodine, bromine.
该方法具体为：按照1:1.0～2.0:0.05～0.2:1.0～3.0的摩尔比取8-卤-1-萘胺类化合物、异腈类衍生物、催化剂和添加剂，将它们置于反应容器中，再在反应容器中加入溶剂至8-卤-1-萘胺类化合物完全溶解；将反应容器置于25-120℃下氮气氛围中搅拌反应0-24h，冷却至室温后，加入与溶剂5倍体积的水后，再用乙酸乙酯萃取2-4次；合并滤液减压蒸馏除去溶剂；经硅胶色谱柱分离，减压蒸馏，即得产物多取代苯并[c,d]吲哚亚胺衍生物。The method is specifically as follows: taking 8-halo-1-naphthylamine compounds, isonitrile derivatives, catalysts and additives in a molar ratio of 1:1.0-2.0:0.05-0.2:1.0-3.0, and placing them in a reaction vessel , and then add solvent to the reaction vessel until the 8-halo-1-naphthylamine compounds are completely dissolved; place the reaction vessel in a nitrogen atmosphere at 25-120 ° C and stir for 0-24 h, after cooling to room temperature, add and solvent After 5 times the volume of water, extract with ethyl acetate for 2-4 times; the combined filtrates are distilled under reduced pressure to remove the solvent; separated by silica gel chromatography and distilled under reduced pressure to obtain the product polysubstituted benzo[c,d]indole imine derivatives.
进一步地，所述8-卤-1-萘胺类化合物可以为8-碘-1-萘胺类化合物(即X为碘)、8-溴-1-萘胺类化合物(即X为溴)；溶剂采用非质子性溶剂。Further, the 8-halo-1-naphthylamine compounds can be 8-iodo-1-naphthylamine compounds (that is, X is iodine), 8-bromo-1-naphthylamine compounds (that is, X is bromine) ; The solvent is an aprotic solvent.
进一步地，所述非质子性溶剂为乙腈、甲苯、四氢呋喃、二氯甲烷、1,2-二氯乙烷、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、N-甲基吡咯烷酮、六甲基磷酰胺或二甲亚砜。Further, the aprotic solvent is acetonitrile, toluene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, N - methylpyrrolidone, hexamethylphosphoramide or dimethyl sulfoxide.
进一步地，所述非质子性溶剂为1,2-二氯乙烷。Further, the aprotic solvent is 1,2-dichloroethane.
进一步地，所述催化剂为Pd(OAc)2、Pd(PPh)4、PdCl2、Pd(PPh3)2Cl2、Pd(TFA)2或Pd2(dba)3，所述催化剂优选为Pd(TFA)2。Further, the catalyst is Pd(OAc) 2 , Pd(PPh) 4 , PdCl 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(TFA) 2 or Pd 2 (dba) 3 , and the catalyst is preferably Pd (TFA) 2 .
进一步地，所述的添加剂为三苯基膦、Cs2CO3、K2CO3、KOH、K3PO4、Na2CO3、NaHCO3、NaOAc、NaOH、DBU、哌啶和吡啶中的一种或多种。Further, the additive is triphenylphosphine, Cs 2 CO 3 , K 2 CO 3 , KOH, K 3 PO 4 , Na 2 CO 3 , NaHCO 3 , NaOAc, NaOH, DBU, piperidine and pyridine one or more.
所述添加剂优选为K2CO3。The additive is preferably K 2 CO 3 .
进一步地，所述反应温度可以为25℃、30℃、40℃、50℃、60℃、70℃、80℃、90℃、100℃、110℃或120℃。Further, the reaction temperature may be 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C or 120°C.
所述反应温度优选为70℃。The reaction temperature is preferably 70°C.
进一步地，所述8-卤-1-萘胺类化合物、异腈类衍生物、催化剂和添加剂的摩尔比为1.0:1.5:0.1:2.0。Further, the molar ratio of the 8-halo-1-naphthylamine compound, the isonitrile derivative, the catalyst and the additive is 1.0:1.5:0.1:2.0.
同现有技术相比，本发明的有益效果为：有利于多取代苯并[c,d]吲哚亚胺衍生物化合物库的建立，为抗肿瘤，抗菌和治疗心脑血管疾病等活性筛选提供了很简便的方法。本发明采用“一锅一步法”合成多取代苯并[c,d]吲哚亚胺衍生物，反应原料简单易得，使用高效的过渡金属作为催化剂，反应条件简单，操作方便，催化量的催化剂就能取得优良的产率，底物普适性广泛，生产成本低廉，不仅适用于实验室小规模制备，还适用于工业化大规模生产。进一步的，可以将多取代苯并[c,d]吲哚亚胺衍生物转化为更多有药用价值和生物活性的分子。Compared with the prior art, the present invention has the following beneficial effects: it is beneficial to the establishment of a compound library of multi-substituted benzo[c,d]indoleimine derivatives, and is used for screening activities such as anti-tumor, antibacterial and treatment of cardiovascular and cerebrovascular diseases. Provides a very simple method. The invention adopts "one-pot one-step method" to synthesize polysubstituted benzo[c,d]indoleimine derivatives, the reaction raw materials are simple and easy to obtain, efficient transition metals are used as catalysts, the reaction conditions are simple, the operation is convenient, and the catalytic amount of The catalyst can achieve excellent yield, wide substrate universality and low production cost, which is not only suitable for small-scale laboratory preparation, but also suitable for industrial large-scale production. Further, the polysubstituted benzo[c,d]indoleimine derivatives can be converted into more molecules with medicinal value and biological activity.
具体实施方式Detailed ways
本发明的多取代苯并[c,d]吲哚亚胺衍生物结构如下所示：The structure of the multi-substituted benzo[c,d]indoleimine derivatives of the present invention is as follows:
其中：R1＝CH3,R2＝H,R3＝H,R4＝t-Bu；R1＝Et,R2＝H,R3＝H,R4＝t-Bu；R1＝p-toluenesulfonyl,R2＝H,R3＝H,R4＝t-Bu；R1＝p-chlorobenzenesulfonyl,R2＝H,R3＝H,R4＝t-Bu；R1＝p-fluorobenzenesulfonyl,R2＝H,R3＝H,R4＝t-Bu；R1＝p-nitrobenzenesulfonyl,R2＝H,R3＝H,R4＝t-Bu；R1＝o-bromobenzenesulfonyl,R2＝H,R3＝H,R4＝t-Bu；R1＝2-naphthalenesulfonyl,R2＝H,R3＝H,R4＝t-Bu；R1＝2-thiophenesulfonyl,R2＝H,R3＝H,R4＝t-Bu；R1＝H,R2＝H,R3＝H,R4＝t-Bu；R1＝H,R2＝CH2,R3＝CH2,R4＝t-Bu；R1＝p-toluenesulfonyl,R2＝CH2,R3＝CH2,R4＝t-Bu；R1＝p-toluenesulfonyl,R2＝NO2,R3＝H,R4＝t-Bu；R1＝p-toluenesulfonyl,R2＝NO2,R3＝NO2,R4＝t-Bu；R1＝p-toluenesulfonyl,R2＝H,R3＝H,R4＝cyclohexyl；R1＝p-toluenesulfonyl,R2＝H,R3＝H,R4＝n-Bu；R1＝p-toluenesulfonyl,R2＝H,R3＝H,R4＝p-nitrophenyl；R1＝H,R2＝H,R3＝H,R4＝p-nitrophenyl；R1＝p-toluenesulfonyl,R2＝H,R3＝H,R4＝phenyl；R1＝p-toluenesulfonyl,R2＝H,R3＝H,R4＝2-naphthyl；R1＝p-toluenesulfonyl,R2＝H,R3＝H,R4＝3,4-dichlorophenyl；R1＝p-toluenesulfonyl,R2＝H,R3＝H,R4＝p-tolyl；R1＝p-toluenesulfonyl,R2＝H,R3＝H,R4＝p-chlorophenyl；R1＝p-toluenesulfonyl,R2＝H,R3＝H,R4＝p-methoxyphenyl；R1＝p-toluenesulfonyl,R2＝H,R3＝H,R4＝p-methoxyphenyl；R1＝p-toluenesulfonyl,R2＝H,R3＝H,R4＝o-chlorophenyl.Wherein: R 1 =CH 3 , R 2 =H, R 3 =H, R 4 =t-Bu; R 1 =Et, R 2 =H, R 3 =H, R 4 =t-Bu; R 1 = p - toluenesulfonyl, R2=H, R3 =H, R4=t - Bu; R1 = p - chlorobenzenesulfonyl, R2=H, R3 =H, R4=t - Bu; R1 = p- fluorobenzenesulfonyl,R 2 =H,R 3 =H,R 4 =t-Bu;R 1 =p-nitrobenzenesulfonyl,R 2 =H,R 3 =H,R 4 =t-Bu;R 1 =o-bromobenzenesulfonyl, R 2 =H, R 3 =H, R 4 =t-Bu; R 1 =2-naphthalenesulfonyl, R 2 =H, R 3 =H, R 4 =t-Bu; R 1 =2-thiophenesulfonyl,R 2 =H,R 3 =H,R 4 =t-Bu;R 1 =H,R 2 =H,R 3 =H,R 4 =t-Bu;R 1 =H,R 2 =CH 2 ,R 3 =CH 2 ,R 4 =t-Bu;R 1 =p-toluenesulfonyl,R 2 =CH 2 ,R 3 =CH 2 ,R 4 =t-Bu;R 1 =p-toluenesulfonyl,R 2 =NO 2 , R 3 =H,R 4 =t-Bu;R 1 =p-toluenesulfonyl,R 2 =NO 2 ,R 3 =NO 2 ,R 4 =t-Bu;R 1 =p-toluenesulfonyl,R 2 =H, R 3 =H,R 4 =cyclohexyl;R 1 =p-toluenesulfonyl,R 2 =H,R 3 =H,R 4 =n-Bu;R 1 =p-toluenesulfonyl,R 2 =H,R 3 =H ,R 4 =p-nitrophenyl;R 1 =H,R 2 =H,R 3 =H,R 4 =p-nitrophenyl;R 1 =p-toluenesulfonyl,R 2 =H,R 3 =H,R 4 = phenyl; R 1 =p-toluenesulfonyl, R 2 =H, R 3 =H, R 4 =2-naphthyl; R 1 =p-toluenesulfonyl,R 2 =H,R 3 =H,R 4 =3, 4-dichlorophenyl; R 1 =p-toluenesulfonyl, R 2 =H, R 3 =H, R 4 =p-tolyl; R 1 =p-toluenesulfonyl, R 2 =H, R 3 =H,R 4 =p- chlorophenyl; R 1 ＝p-toluenesulfonyl,R 2 ＝H,R 3 ＝H,R 4 ＝p-methoxyphenyl;R 1 ＝p-toluenesulfonyl,R 2 ＝H,R 3 ＝H,R 4 ＝p-methoxyphenyl; R 1 =p-toluenesulfonyl, R 2 =H, R 3 =H, R 4 =o-chlorophenyl.
本发明的合成方法是采用“一锅一步法”的合成方式，具体为：按照1.0:1.5:0.1:2.0的摩尔比取8-卤-1-萘胺类化合物、异腈类衍生物、催化剂和添加剂，将它们置于反应容器中，再在反应容器中加入溶剂至8-卤-1-萘胺类化合物完全溶解；将反应容器置于25-120℃下氮气氛围搅拌反应0-24h，冷却至室温后，加入与溶剂5倍体积的水后，再用乙酸乙酯萃取2-4次；合并滤液减压蒸馏除去溶剂；经硅胶色谱柱分离，减压蒸馏，即得产物多取代苯并[c,d]吲哚亚胺衍生物。The synthesis method of the present invention adopts the synthesis method of "one-pot one-step method", specifically: taking 8-halo-1-naphthylamine compounds, isonitrile derivatives, catalysts according to the molar ratio of 1.0:1.5:0.1:2.0 and additives, put them in the reaction container, and then add solvent to the reaction container until the 8-halo-1-naphthylamine compounds are completely dissolved; place the reaction container at 25-120 ° C and stir the reaction in a nitrogen atmosphere for 0-24 h, After cooling to room temperature, add water with 5 times the volume of the solvent, and then extract with ethyl acetate for 2-4 times; combine the filtrates to remove the solvent under reduced pressure; And [c, d] indoleimine derivatives.
本合成方法中，8-卤-1-萘胺类化合物可以为8-碘-1-萘胺类化合物、8-溴-1-萘胺类化合物；溶剂可以采用非质子性溶剂，如乙腈、甲苯、四氢呋喃、二氯甲烷、1,2-二氯乙烷、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、N-甲基吡咯烷酮、六甲基磷酰胺或二甲亚砜中的一种或多种。其中最好的为1,2-二氯乙烷。催化剂可以为Pd(OAc)2、Pd(PPh)4、PdCl2、Pd(PPh3)2Cl2、Pd(TFA)2或Pd2(dba)3中的一种或多种，其中最好的催化剂为Pd(TFA)2。所述添加剂可以为三苯基膦、Cs2CO3、K2CO3、KOH、K3PO4、Na2CO3、NaHCO3、NaOAc、NaOH、DBU、哌啶和吡啶中的一种或多种，其中最好的添加剂为K2CO3。8-卤-1-萘胺类化合物、异腈类衍生物、催化剂和添加剂的摩尔比为1.0:1.5:0.1:2.0。In this synthesis method, the 8-halo-1-naphthylamine compounds can be 8-iodo-1-naphthylamine compounds, 8-bromo-1-naphthylamine compounds; the solvent can be aprotic solvent, such as acetonitrile, Toluene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoramide or dimethy one or more of methyl sulfoxide. The best of them is 1,2-dichloroethane. The catalyst can be one or more of Pd(OAc) 2 , Pd(PPh) 4 , PdCl 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(TFA) 2 or Pd 2 (dba) 3 , among which the best The catalyst is Pd(TFA) 2 . The additive may be one of triphenylphosphine, Cs 2 CO 3 , K 2 CO 3 , KOH, K 3 PO 4 , Na 2 CO 3 , NaHCO 3 , NaOAc, NaOH, DBU, piperidine and pyridine or There are many kinds, among which the best additive is K 2 CO 3 . The molar ratio of 8-halo-1-naphthylamine compound, isonitrile derivative, catalyst and additive is 1.0:1.5:0.1:2.0.
下面通过具体的实施例进一步说明本发明，但并不因此将本发明限制在所述的实施例之中。The present invention is further described below through specific embodiments, but the present invention is not limited to the described embodiments.
表1给出了实施例1-5中多取代苯并[c,d]吲哚亚胺衍生物的结构。Table 1 gives the structures of the polysubstituted benzo[c,d]indolimine derivatives in Examples 1-5.
表1实施例1-5中多取代苯并[c,d]吲哚亚胺衍生物的结构Structures of polysubstituted benzo[c,d]indolimine derivatives in Table 1 Examples 1-5
实施例1～6的原料由已知化合物8-碘(溴)-1-萘胺衍生物制备而来，通过与磺酰氯化合物反应一步制得。The raw materials of Examples 1 to 6 are prepared from the known compound 8-iodo(bromo)-1-naphthylamine derivative, which is prepared by one-step reaction with a sulfonyl chloride compound.
实施例1Example 1
室温下在圆底烧瓶中依次加入N-Ts-8-碘萘胺(0.5mmol)，叔丁基异腈(0.75mmol)，Pd(TFA)2(0.05mmol)，碳酸钾(1.0mmol)和DCE(3ml)，之后在70℃下氮气氛围中搅拌反应直至N-Ts-8-碘萘胺反应完全。反应结束后，冷却至室温，加入与溶剂5倍体积的水后，再用乙酸乙酯萃取2-4次；合并滤液减压蒸馏除去溶剂；经硅胶色谱柱分离，减压蒸馏，即得产物，产率为87％。鉴定结果为：N-Ts-8-iodonaphthylamine (0.5 mmol), tert-butylisonitrile (0.75 mmol), Pd(TFA) 2 (0.05 mmol), potassium carbonate (1.0 mmol) and DCE ( 3 ml), then the reaction was stirred at 70°C under nitrogen atmosphere until the reaction of N-Ts-8-iodonaphthylamine was complete. After the reaction is completed, cool to room temperature, add 5 times the volume of water with the solvent, and then extract with ethyl acetate for 2-4 times; combine the filtrates to remove the solvent under reduced pressure; , the yield was 87%. The identification result is:
黄色固体。Yellow solid.
1H NMR(400MHz,CDCl3)δ7.97–7.85(m,5H),7.62(t,J＝7.8Hz,1H),7.53(d,J＝4.2Hz,2H),7.21(d,J＝8.3Hz,2H),2.38(s,3H),1.40(s,9H)；13C{1H}NMR(100MHz,CDCl3)δ148.1,143.8,138.3,137.0,130.6,128.9,128.7,128.6,128.5,128.2,127.8,126.4,122.9,119.9,109.0,54.4,28.7,21.6；IR(neat)3132,1645,1340,1170,781cm-1；HRMS(ESI-TOF)m/z:[M+H]+Calcd for C22H23N2O2S 379.1480；Found 379.1478. 1 H NMR (400 MHz, CDCl 3 ) δ 7.97-7.85 (m, 5H), 7.62 (t, J=7.8 Hz, 1H), 7.53 (d, J=4.2 Hz, 2H), 7.21 (d, J= 8.3Hz, 2H), 2.38(s, 3H), 1.40(s, 9H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 148.1, 143.8, 138.3, 137.0, 130.6, 128.9, 128.7, 128.6, 128.5 ,128.2,127.8,126.4,122.9,119.9,109.0,54.4,28.7,21.6; IR(neat)3132,1645,1340,1170,781cm -1 ;HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 22 H 23 N 2 O 2 S 379.1480; Found 379.1478.
实施例2Example 2
室温下在圆底烧瓶中依次加入8-碘萘胺(0.3mmol)，叔丁基异腈(0.3mmol)，Pd(OAc)2(0.06mmol)，碳酸铯(0.9mmol)和CH3CN(2ml)，之后在100℃下氮气氛围中搅拌反应直至8-碘萘胺反应完全。反应结束后，冷却至室温，加入与溶剂5倍体积的水后，再用乙酸乙酯萃取2-4次；合并滤液减压蒸馏除去溶剂；经硅胶色谱柱分离，减压蒸馏，即得产物，产率为78％。鉴定结果为：8-Iodonaphthylamine (0.3 mmol), tert-butylisonitrile (0.3 mmol), Pd(OAc) 2 (0.06 mmol), cesium carbonate (0.9 mmol) and CH 3 CN (2 ml) were sequentially added to a round-bottomed flask at room temperature , and then the reaction was stirred under nitrogen atmosphere at 100 °C until the reaction of 8-iodonaphthylamine was complete. After the reaction is completed, cool to room temperature, add 5 times the volume of water with the solvent, and then extract with ethyl acetate for 2-4 times; combine the filtrates to remove the solvent under reduced pressure; , the yield was 78%. The identification result is:
黄色固体。Yellow solid.
1H NMR(400MHz,CDCl3)δ7.88(d,J＝8.4Hz,1H),7.69(d,J＝7.4Hz,1H),7.58–7.50(m,1H),7.49–7.35(m,2H),7.32(d,J＝6.3Hz,1H),1.63(s,9H)；13C{1H}NMR(100MHz,CDCl3)δ133.0,131.2,129.9,129.2,129.1,128.9,127.0,124.3,120.0,119.8,114.5,52.8,29.2；IR(neat)3312,3129,1651,752cm-1；HRMS(ESI-TOF)m/z:[M+H]+Calcd for C15H17N2225.1392；Found 225.1395. 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J=8.4 Hz, 1H), 7.69 (d, J=7.4 Hz, 1H), 7.58-7.50 (m, 1H), 7.49-7.35 (m, 2H), 7.32 (d, J=6.3Hz, 1H), 1.63 (s, 9H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 133.0, 131.2, 129.9, 129.2, 129.1, 128.9, 127.0, 124.3 , 120.0, 119.8, 114.5, 52.8, 29.2; IR (neat) 3312, 3129, 1651, 752 cm -1 ; HRMS (ESI-TOF) m/z: [M+H] + Calcd for C 15 H 17 N 2 225.1392 ;Found 225.1395.
实施例3Example 3
室温下在反应瓶中依次加入8-溴-3,4-环乙基-1-萘胺(1.0mmol)，叔丁基异腈(1.2mmol)，PdCl2(0.05mmol)，碳酸钠(1.0mmol)和DMF(4ml)，之后在120℃下氮气氛围中搅拌反应直至8-溴-3,4-环乙基-1-萘胺反应完全。反应结束后，冷却至室温，加入与溶剂5倍体积的水后，再用乙酸乙酯萃取2-4次；合并滤液减压蒸馏除去溶剂；经硅胶色谱柱分离，减压蒸馏，即得产物，产率为71％。鉴定结果为：8-Bromo-3,4-cycloethyl-1-naphthylamine (1.0 mmol), tert-butylisonitrile (1.2 mmol), PdCl 2 (0.05 mmol), and sodium carbonate (1.0 mmol) were successively added to the reaction flask at room temperature and DMF (4 ml), then the reaction was stirred at 120°C under nitrogen atmosphere until the 8-bromo-3,4-cycloethyl-1-naphthylamine reaction was complete. After the reaction is completed, cool to room temperature, add 5 times the volume of water with the solvent, and then extract with ethyl acetate for 2-4 times; combine the filtrates to remove the solvent under reduced pressure; , the yield was 71%. The identification result is:
黄色固体。Yellow solid.
1H NMR(400MHz,CDCl3)δ7.75(d,J＝6.7Hz,1H),7.39–7.27(m,2H),7.18(d,J＝6.8Hz,1H),3.50–3.37(m,4H),1.62(s,9H)；13C{1H}NMR(100MHz,CDCl3)δ162.8,159.3,149.0,138.6,136.6,127.3,123.3,121.4,120.6,119.0,115.6,52.8,33.3,32.0,29.2；IR(neat)3315,3128,1653,1471,762cm-1；HRMS(ESI-TOF)m/z:[M+H]+Calcd for C17H19N2251.1548；Found 251.1546. 1 H NMR (400 MHz, CDCl 3 ) δ 7.75 (d, J=6.7 Hz, 1H), 7.39-7.27 (m, 2H), 7.18 (d, J=6.8 Hz, 1H), 3.50-3.37 (m, 4H), 1.62(s, 9H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 162.8, 159.3, 149.0, 138.6, 136.6, 127.3, 123.3, 121.4, 120.6, 119.0, 115.6, 52.8, 33.3, 32.0 , 29.2; IR (neat) 3315, 3128, 1653, 1471, 762 cm -1 ; HRMS (ESI-TOF) m/z: [M+H] + Calcd for C 17 H 19 N 2 251.1548; Found 251.1546.
实施例4Example 4
室温下在圆底烧瓶中依次加入N-Ts-8-溴萘胺(0.2mmol)，环己基异腈(0.26mmol)，Pd(PPh)4(0.04mmol)，NaOH(0.5mmol)和DMAc(3ml)，之后在110℃下氮气氛围中搅拌反应直至N-Ts-8-溴萘胺反应完全。反应结束后，冷却至室温，加入与溶剂5倍体积的水后，再用乙酸乙酯萃取2-4次；合并滤液减压蒸馏除去溶剂；经硅胶色谱柱分离，减压蒸馏，即得产物，产率为65％。鉴定结果为：N-Ts-8-bromonaphthylamine (0.2 mmol), cyclohexylisonitrile (0.26 mmol), Pd(PPh) 4 (0.04 mmol), NaOH (0.5 mmol) and DMAc ( 3 ml), then the reaction was stirred at 110°C under nitrogen atmosphere until the reaction of N-Ts-8-bromonaphthylamine was complete. After the reaction is completed, cool to room temperature, add 5 times the volume of water with the solvent, and then extract with ethyl acetate for 2-4 times; combine the filtrates to remove the solvent under reduced pressure; , the yield is 65%. The identification result is:
黄色固体。Yellow solid.
1H NMR(400MHz,CDCl3)δ7.91(d,J＝8.1Hz,2H),7.85(d,J＝8.2Hz,1H),7.81(d,J＝7.2Hz,1H),7.55(t,J＝7.5Hz,1H),7.52–7.44(m,2H),7.24–7.13(m,3H),3.73(t,J＝6.7Hz,2H),2.32(s,3H),1.71–1.62(m,2H),1.38–1.28(m,2H),0.89(t,J＝7.3Hz,3H)；13C{1H}NMR(100MHz,CDCl3)δ151.5,144.3,138.5,136.2,130.5,129.1,129.0,128.8,128.6,128.2,127.1,124.8,124.1,120.1,109.3,50.7,33.3,21.6,20.6,14.0；IR(neat)3128,1635,1346,1176,755cm-1；HRMS(ESI-TOF)m/z:[M+H]+Calcd for C24H25N2O2S 405.1637；Found 405.1639. 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (d, J=8.1 Hz, 2H), 7.85 (d, J=8.2 Hz, 1H), 7.81 (d, J=7.2 Hz, 1H), 7.55 (t , J=7.5Hz, 1H), 7.52–7.44 (m, 2H), 7.24–7.13 (m, 3H), 3.73 (t, J=6.7Hz, 2H), 2.32 (s, 3H), 1.71–1.62 ( m, 2H), 1.38–1.28 (m, 2H), 0.89 (t, J=7.3 Hz, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 151.5, 144.3, 138.5, 136.2, 130.5, 129.1 , 129.0, 128.8, 128.6, 128.2, 127.1 , 124.8, 124.1, 120.1, 109.3, 50.7, 33.3, 21.6, 20.6, 14.0; )m/z: [M+H] + Calcd for C 24 H 25 N 2 O 2 S 405.1637; Found 405.1639.
实施例5Example 5
室温下在反应瓶中依次加入N-Ts-4-硝基-8-碘萘胺(0.6mmol)，叔丁基异腈(1.2mmol)，Pd2(dba)3(0.09mmol)，NaHCO3(1.8mmol)和DMSO(3ml)，之后在90℃下氮气氛围中搅拌反应直至N-Ts-4-硝基-8-碘萘胺反应完全。反应结束后，冷却至室温，加入与溶剂5倍体积的水后，再用乙酸乙酯萃取2-4次；合并滤液减压蒸馏除去溶剂；经硅胶色谱柱分离，减压蒸馏，即得产物，产率为72％。鉴定结果为：N-Ts-4-nitro-8-iodonaphthylamine (0.6 mmol), tert-butylisonitrile (1.2 mmol), Pd 2 (dba) 3 (0.09 mmol), NaHCO 3 (1.8 mmol) were successively added to the reaction flask at room temperature mmol) and DMSO (3 ml), then the reaction was stirred at 90°C under nitrogen atmosphere until N-Ts-4-nitro-8-iodonaphthylamine reaction was complete. After the reaction is completed, cool to room temperature, add 5 times the volume of water with the solvent, and then extract with ethyl acetate for 2-4 times; combine the filtrates to remove the solvent under reduced pressure; , the yield was 72%. The identification result is:
黄色固体。Yellow solid.
1H NMR(400MHz,CDCl3)δ8.50(d,J＝7.6Hz,1H),8.33(d,J＝7.8Hz,1H),8.10(d,J＝6.7Hz,1H),6.79–6.66(m,1H),4.24–4.08(m,2H),4.04–3.83(m,2H),1.75–1.65(m,4H),1.58(s,9H),1.48–1.33(m,4H),1.00–0.97(m,2H),0.97–0.93(m,4H)；13C{1H}NMR(100MHz,CDCl3)δ163.9,163.8,161.8,135.5,130.9,130.7,130.6,129.4,128.8,127.8,126.3,126.2,126.0,40.9,40.0,30.5,30.2,29.7,29.4,20.4,20.1,13.9,13.8；IR(neat)3129,1632,1535,1345,1163,756cm-1；HRMS(ESI-TOF)m/z:[M+H]+Calcd for C22H22N3O4S424.1331；Found 424.1330. 1 H NMR (400 MHz, CDCl 3 ) δ 8.50 (d, J=7.6 Hz, 1H), 8.33 (d, J=7.8 Hz, 1H), 8.10 (d, J=6.7 Hz, 1H), 6.79-6.66 (m, 1H), 4.24–4.08 (m, 2H), 4.04–3.83 (m, 2H), 1.75–1.65 (m, 4H), 1.58 (s, 9H), 1.48–1.33 (m, 4H), 1.00 -0.97(m, 2H), 0.97-0.93(m, 4H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 163.9, 163.8, 161.8, 135.5, 130.9, 130.7, 130.6, 129.4, 128.8, 127.8, 126.3, 126.2, 126.0, 40.9, 40.0, 30.5, 30.2, 29.7, 29.4, 20.4, 20.1, 13.9, 13.8; IR (neat) 3129, 1632, 1535, 1345, 1163, 756cm -1 ; HRMS (ESI-TOF) m/z: [M+H] + Calcd for C 22 H 22 N 3 O 4 S424.1331; Found 424.1330.
实施例6Example 6
室温下在反应瓶中依次加入8-碘萘胺(0.4mmol)，对硝基苯基异腈(0.7mmol)，Pd(PPh3)2Cl2(0.06mmol)，K2CO3(0.7mmol)和DMSO(2ml)，之后在100℃下氮气氛围中搅拌反应直至8-碘萘胺反应完全。反应结束后，冷却至室温，加入与溶剂5倍体积的水后，再用乙酸乙酯萃取2-4次；合并滤液减压蒸馏除去溶剂；经硅胶色谱柱分离，减压蒸馏，即得产物，产率为56％。鉴定结果为：8-Iodonaphthylamine (0.4 mmol), p-nitrophenyl isonitrile (0.7 mmol), Pd(PPh 3 ) 2 Cl 2 (0.06 mmol), K 2 CO 3 (0.7 mmol) were sequentially added to the reaction flask at room temperature ) and DMSO (2 ml), then the reaction was stirred at 100°C under nitrogen atmosphere until the 8-iodonaphthylamine reaction was complete. After the reaction is completed, cool to room temperature, add 5 times the volume of water with the solvent, and then extract with ethyl acetate for 2-4 times; combine the filtrates to remove the solvent under reduced pressure; , the yield is 56%. The identification result is:
黄色固体。Yellow solid.
1H NMR(400MHz,d6-DMSO)δ9.10(s,1H),8.58–8.37(m,3H),8.34–7.84(m,5H),7.81–7.66(m,1H),7.66–7.36(m,1H)；13C{1H}NMR(100MHz,d6-DMSO)δ157.6,144.6,141.4,133.0,129.9,129.6,129.4,128.3,127.3,126.8,125.6,125.4,123.6,122.8,112.8；IR(neat)3130,1636,1351,758cm-1；HRMS(ESI-TOF)m/z:[M+H]+Calcd for C17H12N3O2290.0930；Found 290.0929，CAS号：1203674-69-4。 1 H NMR(400MHz,d6-DMSO)δ9.10(s,1H),8.58-8.37(m,3H),8.34-7.84(m,5H),7.81-7.66(m,1H),7.66-7.36( m,1H);13C{1H}NMR(100MHz,d6-DMSO)δ157.6,144.6,141.4,133.0,129.9,129.6,129.4,128.3,127.3,126.8,125.6,125.4,123.6,122.8,112.8;IR(neat ) 3130,1636,1351,758cm -1 ; HRMS(ESI-TOF) m/z: [M+H] + Calcd for C 17 H 12 N 3 O 2 290.0930; Found 290.0929, CAS No.: 1203674-69-4 .
上述实施例用来解释说明本发明，而不是对本发明进行限制，在本发明的精神和权利要求的保护范围内，对本发明作出的任何修改和改变，都落入本发明的保护范围。The above-mentioned embodiments are used to explain the present invention, rather than limit the present invention. Within the spirit of the present invention and the protection scope of the claims, any modifications and changes made to the present invention all fall into the protection scope of the present invention.
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